Brevetoxins are a type of neurotoxin produced in red tide blooms. Northern quahogs (M. mercenaria) are extensively used in commercial aquaculture farming, and early-stage metabolomics studies can provide early warnings of brevetoxins for farmers. In this study, NMR-based metabolomics was performed to investigate the response of clam gills and digestive glands under a series of sublethal doses of brevetoxins. Our study showed that the brevetoxin PbTx-2 had minimal influence on the physical activities of M. mercenaria for a short exposure time (24 hours). However, major metabolic level perturbations were observed in the clam gill extracts from the 1 ppb treatment. In addition, in the low concentration (0.1 ppb) study, clam gills showed combinational metabolite perturbations, as observed by an OPLS-DA study. The highly disturbed metabolites in the gill samples were the upregulated serine, glucose, hypotaurine, and glycine and the downregulated lactate, leucine, isoleucine, threonine, biotin, taurine, and valine. The results indicated that the brevetoxin PbTx-2 potentially affects glycolysis, glycine, serine, and threonine metabolism, taurine and hypotaurine metabolism, and biotin metabolism. While the digestive gland had less significantly changed metabolites, the potential combinational metabolite changes from PCA were observed from the 5-ppb treatment. Glucose and glycine are the primary metabolites that showed high contributions to the OPLS-DA model, which indicates the potential influence of digestive activities. The study indicated that metabolomic analysis of the gills and digestive glands of M. mercenaria is a feasible method to monitor the toxicity of brevetoxins, especially under sublethal doses in marine water.